Injectable pharmaceutical compositions for the treatment of joints

ABSTRACT

The present invention relates to an injectable pharmaceutical formulation for the alleviation or reduction of joint irritation or for the reduction of worsening of existing joint inflammation, formulated for intra-articular injection comprising an active polyol ingredient, which polyol active ingredient is xylitol. Use of the intra-articular injectable formulations for the treatment of joint diseases or conditions including arthritis is described.

FIELD OF THE INVENTION

The present invention relates to an injectable pharmaceuticalformulation for the alleviation or reduction of joint irritation or forthe reduction of worsening of existing joint inflammation, formulatedfor intra-articular injection.

BACKGROUND OF THE INVENTION

Articular and/or joint cartilage damages are injuries or lesions causedby various means, such as ageing, mechanical, chemical, viral,bacterial, fungal and other pathogenic organisms, which affects jointtissue structures. The result is pain, swelling or both.

Wound repair consists of a series of processes whereby injured tissue isrepaired, inflammation or irritation is reduced, specialized tissue isregenerated, and new tissue is reorganized partially or completely andclinical improvements are observed.

Tissue repair is a dynamic pathway that affects tissue integrity andfunction. Tissue repairing pathways are set into motion at the moment oftissue damage or irritation. Tissue repairing is the result of theaccumulation of processes, including inflammation, ground substance andmatrix synthesis, angiogenesis, fibroplasia, epithelialization,remodeling and influences tissue and cellular biochemistry.

DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide an injectablepharmaceutical formulation for the alleviation or reduction of jointirritation or inflammation, for the alleviation or reduction of or forthe reduction of worsening of existing joint inflammation as a result offurther irritation, or for the alleviation or reduction of arthritis,formulated for intra-articular injection.

More particularly, according to the present invention, there is nowprovided an injectable pharmaceutical formulation for the prevention ofjoint irritation or worsening of existing joint inflammation as a resultof further irritation, formulated for intra-articular injection,comprising Xylitol as active ingredient therein.

In some embodiments, this invention provides an injectablepharmaceutical formulation for the alleviation or reduction of jointirritation or for the reduction of worsening of existing jointinflammation as a result of further irritation, formulated forintra-articular injection, comprising an active polyol ingredient, whichpolyol active ingredient is Xylitol.

In some embodiments of the present invention the Xylitol is D-xylitol.In some embodiments of the present invention the Xylitol is L-xylitol orin some embodiments, the xylitol is D,L-xylitol.

In some embodiments of the present invention said concentration ofXylitol is between 0.5% and 10% in water.

In some embodiments said pharmaceutical formulation contains at leastone polymer.

In some embodiments of the present invention said pharmaceuticalformulation further comprises an anionic polymer with molecular weighthigher than 500,000 dalton in order to provide the formulation withnon-newtonian shear thinning viscosity.

It is known that anionic polymers such as sodium hyaluronate in thepresence of inorganic salts such as phosphate buffer, exhibit aNewtonian viscosity profile.

The Advantage of a non-newtonian shear thinning viscosity profile isthat when force is applied to the same, the viscosity immediately andprecipitously drops. In accordance with this, when the stickinessbetween two pieces of human cartilage was measured in vitro with 1%sodium hyaluronate between them, the non-Newtonian (salt free)formulation was less sticky than the usual formulations.

In 24 measurements (Load: 10N, speed of movement 1 mm/sec., temperature36-37° C.) the dynamic viscosity coefficient of the non-Newtonian(isotonicity by polyol) formulation was 0.03759±0.01481, whereas thedynamic viscosity of the Newtonian formulation (isotonicity by 0.9%sodium chloride) was 0.04892±0.01370, namely, more sticky. In someembodiments of the present invention the concentration of neutralizedhyaluronic acid is 0.1% to 5%.

In one embodiment of the present invention said anionic polymer is inthe form of a salt thereof and said formulation contains less than 0.01%of any inorganic salt.

In some embodiments of the present invention said pharmaceuticalformulation is substantially devoid of any oil in water or wax in wateremulsion.

In other embodiments of the present invention said Xylitol is inisotonic concentration.

In other embodiments, said pharmaceutical formulation further comprisesat least one pharmaceutically acceptable excipient or additive.

In other embodiments said pharmaceutical formulation further comprisesat least one further pharmaceutical agent selected from the groupconsisting of an anti-inflammatory agent, an antioxidant, a vitamin,another polyol and combinations thereof.

In one embodiment, the composition further comprises ananti-inflammatory agent such as betamethasone, prednisolone, piroxicam,aspirin, flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyureasalsalate, diflunisal, ibuprofen, fenoprofen, fenamate, ketoprofen,nabumetone, naproxen, diclofenac, indomethacin, sulindac, tolmetin,etodolac, ketorolac, oxaprozin, or celecoxib; an antiviral such asacyclovir, nelfinavir, or virazole; an antibiotic such as ampicillin andpenicillin G or belonging to the family of penicillines, cephalosporins,aminoglycosidics, macrolides, carbapenem and penem, beta-lactammonocyclic, inhibitors of beta-lactamases, tetracyclins, polipeptidicantibiotics, chloramphenicol and derivatives, fusidic acid, lincomicyn,novobiocine, spectinomycin, poly-etheric ionophores, quinolones; ananti-infective such as benzalkonium chloride or chlorhexidine; dapsone,chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradineerythromycin, clindamycin, lincomycin, amoxicillin, ampicillin,bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin,hetacillin, methicillin, nafcillin, oxacillin, penicillin includingpenicillin G and penicillin V, ticarcillin rifampin and tetracycline; anantiinflammatory such as diflunisal, ibuprofen, indomethacin,meclofenamate, mefenamic acid, naproxen, oxyphenbutazone,phenylbutazone, piroxicam, sulindac, tolmetin, aspirin and salicylates,phytosphingosine type agents or a combination thereof.

In one embodiment, the composition further comprises a steroid. In oneembodiment, the term “steroid” refers to naturally occurring steroidsand their derivatives as well as synthetic or semi-synthetic steroidanalogues having steroid-like activity. In one embodiment, the steroidis a glucocorticoid or corticosteroid. For example, many such steroidshave a core fused ring structure based on cyclopentanophenanthrene.Examples of specific natural and synthetic steroids include, but are notlimited to: aldosterone, beclomethasone, betamethasone, budesonide,cloprednol, cortisone, cortivazol, deoxycortone, desonide,desoximetasone, dexamethasone, difluorocortolone, fluclorolone,flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl,fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone,fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, 25methylprednisolone, paramethasone, prednisolone, prednisone, tixocortolor triamcinolone, and their respective pharmaceutically acceptable saltsor derivatives. It will be appreciated that combinations of suchsteroids may also be used in accordance with this invention.

In other embodiments, the present invention is directed to the use ofXylitol in the manufacture of an injectable pharmaceutical formulation,formulated for intra-articular injection, for the alleviation orreduction of joint irritation or of the worsening of existing jointinflammation.

While Xyliltol is known in the prior art as a topical anti-irritant, itcould not be predicted, nor was it obvious, that it would be effectivefor the prevention of joint irritation or worsening of existing jointinflammation when formulated for intra-articular injection. This isespecially so since the joints of the body are known to be differentthan all other structures in the body in that they are lined withsynovial membranes and are the only structures in the body havinghyaline cartilage.

Furthermore, as is known, joints exhibit a different rate of absorptionthan any other structure in the body and therefore the effect of aspecific compound on the joints cannot be learned from the effect ofsaid compound elsewhere in the body.

For alleviating or reducing irritation or the worsening of existingjoint inflammation, the preferred formulation might contain a polymerfor example: Carbomer, Hyaluronate, Carboxy Methyl Cellulose, hydroxylpropyl methyl cellulose, polyvinyl alcohol or similar. To achievenon-newtonian property of the injection, an anionic polymer is used andas stated above, the formulation will not contain any significantconcentration of an inorganic salt, other than the salt of said anionicpolymer, in order to prevent interference with the property ofnon-newtonian shear thinning viscosity.

One embodied method to achieve non-newtonian shear thinning viscosityproperty is to inject a preparation with isotonic xylitol and 1% sodiumHyaluronate.

The sterile solution might be portioned in vials or in single injectionsor any other convenient way for practical use.

In some embodiments, the term “contacting” or “administering” refers toboth direct and indirect exposure to the indicated material.

In some embodiments, the compositions and/or methods of this inventioncomprise or make use of a non-sterile or sterile carrier or carriers foradministration to cells, tissues or organisms, such as a pharmaceuticalcarrier suitable for administration to an individual. Such carriers mayinclude, but are not limited to, saline, buffered saline, dextrose,water, glycerol, and combinations thereof.

In some embodiments, the compositions and/or methods of this inventioncomprise or make use of pharmaceutically acceptable carriers, which maybe aqueous or non-aqueous solutions, suspensions, emulsions or oils.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, and injectable organic esters such as ethyl oleate. Aqueouscarriers include water, alcoholic/aqueous solutions, emulsions orsuspensions, including saline and buffered media. Examples of oils arethose of petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, andfish-liver oil.

In addition, the compositions of this invention may further comprisebinders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose,guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,povidone), disintegrating agents (e.g., cornstarch, potato starch,alginic acid, silicon dioxide, croscarmelose sodium, crospovidone, guargum, sodium starch glycolate), buffers (e.g., Tris-HCl, acetate,phosphate) of various pH and ionic strength, additives such as albuminor gelatin to prevent absorption to surfaces, detergents (e.g., Tween20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors,surfactants (e.g., sodium lauryl sulfate), permeation enhancers,solubilizing agents (e.g., glycerol, polyethylene glycerol),anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylatedhydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose,hyroxypropylmethyl cellulose), viscosity increasing agents (e.g.,carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum),sweeteners (e.g., aspartame, citric acid), preservatives (e.g.,Thimerosal, benzyl alcohol, parabens), lubricants (e.g., stearic acid,magnesium stearate, polyethylene glycol, sodium lauryl sulfate),flow-aids (e.g., colloidal silicon dioxide), plasticizers (e.g., diethylphthalate, triethyl citrate), emulsifiers (e.g., carbomer, hydroxypropylcellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers orpoloxamines), coating and film forming agents (e.g., ethyl cellulose,acrylates, polymethacrylates) and/or adjuvants.

Solid carriers/diluents include, but are not limited to, a gum, a starch(e.g., corn starch, pregeletanized starch), a sugar (e.g., lactose,mannitol, sucrose, dextrose), a cellulosic material (e.g.,microcrystalline cellulose), an acrylate (e.g., polymethylacrylate),calcium carbonate, magnesium oxide, talc, or mixtures thereof.

In one embodiment, compositions of this invention are pharmaceuticallyacceptable. In one embodiment, the term “pharmaceutically acceptable”refers to any formulation which is safe, and provides the appropriatedelivery for the desired route of administration of an effective amountof at least one compound for use in the present invention. This termrefers to the use of buffered formulations as well, wherein the pH ismaintained at a particular desired value, ranging from pH 4.0 to pH 9.0,in accordance with the stability of the compounds and route ofadministration.

In one embodiment, suitable pharmaceutically acceptable carriers includebut are not limited to water, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, polyethylene glycols, gelatine,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, silicic acid, viscous paraffin, white paraffin, glycerol,alginates, hyaluronic acid, collagen, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy methylcellulose, polyvinyl pyrrolidone, etc. In anotherembodiment, the pharmaceutical preparations can be sterilized and ifdesired mixed with auxiliary agents, e.g., lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, flavoring and/or aromatic substances andthe like which do not deleteriously react with the active compounds. Inanother embodiment, they can also be combined where desired with otheractive agents, e.g., vitamins.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compositions, use andpreparations of the present invention without departing from the spiritor scope of the invention.

For administration to mammals, and particularly humans, it is expectedthat in the case of medications, the physician or other qualifiedhealthcare provider may determine the actual dosage and duration oftreatment, which will be most suitable for an individual and can varywith the age, weight and response of the particular individual.

In some embodiments, any of the compositions of this invention willcomprise an active polyol ingredient, which polyol active ingredient isXylitol in any form or embodiment as described herein. In someembodiments, any of the compositions of this invention will consist ofan active polyol ingredient, which polyol active ingredient is Xylitol,in any form or embodiment as described herein. In some embodiments, anyof the compositions of this invention will consist essentially of anactive polyol ingredient, which polyol active ingredient is Xylitol, inany form or embodiment as described herein.

In some embodiments, the term “comprise” refers to the inclusion of theindicated active agent, such as the Xylitol, as well as inclusion ofother active agents, and pharmaceutically acceptable carriers,excipients, emollients, stabilizers, etc., as are known in thepharmaceutical industry.

In some embodiments, the compositions of this invention will consistessentially of an active polyol ingredient, which polyol activeingredient is Xylitol as herein described. In some embodiments, the term“consisting essentially of” refers to a composition whose only activeingredient of a particular class of agents, is the indicated activeingredient, i.e. the only active polyol is Xylitol, however, othercompounds may be included which are involved directly in the therapeuticeffect of the indicated active ingredient. In some embodiments, withreference to the compositions of this invention, when referring to acomposition consisting essentially of an active polyol ingredient, whichpolyol active ingredient is Xylitol, such reference specificallyexcludes the incorporation of more than 0.01% inorganic salt in thecomposition, in order to achieve a formulation exhibiting non-Newtonianshear thinning viscosity.

In some embodiments, the term “consisting essentially of” refers to acomposition whose only active ingredient of targeting a particularmechanism, or acting via a particular pathway, is the indicated activeingredient, however, other compounds may be included which are involveddirectly in the therapeutic effect of the indicated active ingredient,which for example have a mechanism of action related to but not directlyto that of the indicated agent.

For example, and representing an embodiment of this invention, thecompositions of this invention consisting essentially of an activepolyol ingredient, which polyol active ingredient is Xylitol may consistfurther of an anti-inflammatory or anti-infective agent, which agentsassist in treating a joint condition, but which secondary treatment isunrelated to the effect of the Xylitol.

In some embodiments, the term “consisting essentially of” refers to acomposition whose only active ingredient is the indicated activeingredient, however, other compounds may be included which are forstabilizing, preserving, etc. the formulation, but are not involveddirectly in the therapeutic effect of the indicated active ingredient.In some embodiments, the term “consisting essentially of” may refer tocomponents which facilitate the release of the active ingredient. Insome embodiments, the term “consisting” refers to a composition, whichcontains the active ingredient and a pharmaceutically acceptable carrieror excipient.

Although the pharmaceutical compositions provided herein are principallydirected to pharmaceutical compositions which are suitable foradministration to humans, it will be understood by the skilled artisanthat such compositions are generally suitable for administration toanimals of all sorts. Modification of pharmaceutical compositionsuitable for administration to humans in order to render thecompositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and perform such modification with little, if any,experimentation. Subjects to which administration of the pharmaceuticalcompositions of the invention is contemplated include, but are notlimited to, humans and other primates, and other mammals.

In some embodiments, this invention provides a method of treating ajoint disease, disorder or condition, said method comprising injecting apharmaceutical composition into an affected joint tissue, wherein saidcomposition comprises a polyol, which polyol is xylitol and an anionicpolymer, wherein said composition exhibits non-Newtonian shear thinningviscosity. In some embodiments, this invention provides for the use of apolyol, which polyol is xylitol and an anionic polymer in themanufacture of an injectable pharmaceutical formulation, formulated forintra-articular injection, which composition exhibits non-Newtonianshear thinning viscosity for the alleviation or reduction of jointirritation or for the reduction of worsening of existing jointinflammation.

In some embodiments, this invention provides a method of treating ajoint disease, disorder disease, disorder or condition, said methodcomprising injecting a pharmaceutical composition into an affected jointtissue, wherein said composition comprises xylitol and optionally atleast a second therapeutic agent, wherein said second therapeutic agentcomprises an anionic polymer, an anti-inflammatory agent, anantioxidant, a vitamin, a second polyol or combinations thereof.

In some embodiments, this invention provides for the use of xylitol andoptionally at least a second therapeutic agent, wherein said secondtherapeutic agent comprises an anionic polymer, an anti-inflammatoryagent, an antioxidant, a vitamin, a second polyol or combinationsthereof in the manufacture of an injectable pharmaceutical formulation,formulated for intra-articular injection, which composition exhibitsnon-Newtonian shear thinning viscosity for the alleviation or reductionof joint irritation or for the reduction of worsening of existing jointinflammation.

In one embodiment, the compositions of the invention may be administeredacutely for acute treatment of temporary conditions, or may beadministered chronically, especially in the case of progressive,recurrent, or degenerative disease. In one embodiment, one or morecompounds of the invention may be administered simultaneously, or inanother embodiment, they may be administered in a staggered fashion. Inone embodiment, the staggered fashion may be dictated by the stage orphase of the disease.

As used herein, the term “treating” includes preventive as well asdisorder remittive treatment. In some embodiments, the methods oftreatment/uses of the compositions as described herein for treating ajoint condition, disease or disorder, include reducing, suppressing orinhibiting the same. In some embodiments, the terms “reducing”,“suppressing” and “inhibiting” have their commonly understood meaning oflessening or decreasing. In some embodiments, the methods oftreatment/uses of the compositions as described herein for treating ajoint condition, disease or disorder, include halting diseaseprogression. As used herein, the term “progression” means increasing inscope or severity, advancing, growing or becoming worse. In someembodiments, the methods of treatment/uses of the compositions asdescribed herein for treating a joint condition, disease or disorder,include preventing disease recurrence. As used herein, the term“recurrence” means the return of a disease after a remission.

As used herein, the term “administering” refers to bringing a subject incontact with a compound of the present invention. As used herein,administration can be accomplished in vitro, i.e. in a test tube, or invivo, i.e. in cells or tissues of living organisms, for example humans.In one embodiment, the present invention encompasses administering thecompounds of the present invention to a subject.

In some embodiments, the compositions, methods and/or uses of thisinvention provide a means for the alleviation or reduction of jointirritation and/or the alleviation or reduction of joint inflammation,and/or the alleviation or reduction of articular cartilage damage,and/or the alleviation or reduction of arthritis.

In one embodiment, “preventing, or treating” refers to any one or moreof the following: delaying the onset of symptoms, reducing the severityof symptoms, reducing the severity of an acute episode, reducing thenumber of symptoms, reducing the incidence of disease-related symptoms,reducing the latency of symptoms, ameliorating symptoms, reducingsecondary symptoms, reducing secondary infections, prolonging patientsurvival, preventing relapse to a disease, decreasing the number orfrequency of relapse episodes, increasing latency between symptomaticepisodes, increasing time to sustained progression, expeditingremission, inducing remission, augmenting remission, speeding recovery,or increasing efficacy of or decreasing resistance to alternativetherapeutics. In one embodiment, “treating” refers to both therapeutictreatment and prophylactic or preventive measures, wherein the object isto prevent or lessen the targeted pathologic condition or disorder asdescribed hereinabove.

In another embodiment, “symptoms” may be any manifestation of a diseaseor pathological condition as described hereinabove.

The administration mode of the compounds and compositions of the presentinvention, timing of administration and dosage, i.e. the treatmentregimen, will depend on the type and severity of the disease and the ageand condition of the subject. In one embodiment, the compounds andcompositions may be administered concomitantly. In another embodiment,the compounds and compositions may be administered at time intervals ofseconds, minutes, hours, days, weeks or more.

While the invention will now be described in connection with certainpreferred embodiments in the following examples so that aspects thereofmay be more fully understood and appreciated, it is not intended tolimit the invention of these particular embodiments. On the contrary, itis intended to cover all alternatives, modifications and equivalents asmay be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of proving what isbelieved to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLES Example 1 Intra-Articular Injection with Hyaluronate HavingNon-Newtonian Viscosity Property

Hyaluronate  1 gm Xylitol  4.5 gm Water to 100 gmpH adjusted to about 7.0It is to be used by single or serial injections.It is very viscous, but because of the non-newtonian shear thinningviscosity property, it is easy to inject. It also has lubricant action.

Example 2 Intra-Articular Injection without Hyaluronate

Xylitol  4.5 gm Water to 100 gmpH adjusted to about 7.0It is to be used by single or serial injections.

Example 3 Intra-Articular Injection with Lipid

Xylitol  4.5 gm Lecithin emulsion  1 gm Water to 100 gmpH adjusted to about 7.0It is to be used by single or serial injections.The lecithin provides lubrication.

Example 4 Intra-Articular Injection with Hyaluronate

Hyaluronate 1 gm Xylitol 3 gm Buffered saline 0.3 gm   Water to 100 gm pH adjusted to about 7.0It is to be used by single or serial injections.

Example 5 Intra-Articular Injection with an Anti-Inflammatory Agent

Xylitol 4.5 gm Methyl predinsolone acetate 4 gm (in suspension) Bufferedsaline 0.3 gm Water to 100 gmpH adjusted to about 7.0It is to be used by single or serial injections.

Example 6 Intra-Articular Injection with Non-Steroidal Anti-InflammatoryAgent

Xylitol 3.0 gm Diclofenac sodium 0.3 gm Buffered saline 0.3 gm Water to100 gm pH adjusted to about 7.0It is to be used by single or serial injections.

Example 7 Treatment of Arthritic or Arthrotic Joints

The knee joints of the hind legs of rabbits weighing 2-3 Kg., wereinjected with sterile solutions prepared according to the above examplesand as described in the table below. After 24 hours the rabbits weresacrificed, the joints were removed and histological studies of thesynnovial membrane were carried out.

Each of the following histological findings was scored 0 to 3.

a. Synovial lining hyperplasia

b. Presence of Fibrin

c. Inflammatory infiltration

d. Necrosis

Signs of serious irritation and inflammation by injecting 0.25 ml of0.5% SLS were found (see Table 1). When certain compounds with 0.25 mlof 0.5% SLS were injected, alleviation of the damage to the synovialmembrane was found.

Results

TABLE 1 0.25 ml of 0.5% SLS treatment per rabbit's knee - Standard errorsacrifice 24 h after intra-articular injection Mean of the mean Saline(negative control) 1.4 0.4 0.2% SLS in saline 1.4 0.3 0.5% SLS in saline(positive control) 5.8 1.0 5.4% Mannitol in distilled water 3.4 0.6 4.5%Xylitol in distilled water 1.4 0.4 1% sodium Hyaluronate in saline 1.00.4 0.5% SLS in 1% sodium Hyaluronate in saline 0.8 0.4 0.5% SLS in 4.5%xylitol in distilled water 0.4 0.8 SLS = sodium lauryl sulphate

Referring to the results in the above table, it will be noted that aninjection of 0.5% SLS in saline gave a result of 5.8, which is thehighest irritation result, while injection of only saline gave a resultof 1.4 which is considered to be the norm without irritation orinflammation.

In the next to last row of the table, there is shown the results ofinjection 0.5% SLS in combination with 1% sodium hyaluronate in saline,which is a known anti-irritant, anti-inflammatory agent and the resultis 0.8 which is not significantly different than the result for thesaline negative control by itself.

As will be noted, in the last row of the table, there is shown theresults of injection of 0.5% SLS in 4.5% Xylitol in distilled water,wherein the result is 0.4, which is also not significantly differentthan the result of the saline negative control by itself and whichproves that indeed Xylitol is surprisingly effective in this context.

As will be noted from row 4 of said table, Mannitol, which has structuresimilar to that of Xyliltol, and which therefore would be expected tofunction in a similar manner, by itself in distilled water, gave aresult of 3.4 showing that it does not prevent irritation, when injectedby intra-articular injection into a rabbit's knee. Similarly, lack ofprevention of irritation is shown by some other polyols (e.g. glycerolor glucitol) tested in comparable circumstances (data not shown).

For this reason also, it is surprising and could not be predicted thatXylitol, formulated for intra-articular injection, would be effectivefor the prevention of joint irritation or worsening of existing jointinflammation as a result of further irritation.

Example 8 Comparative Frictional Coefficients in Human Cartilage Samplesin the Presence of Different Lubricants

Human cartilage samples were obtained and a human joint friction testwas conducted as described in Merkher Y. et. al., (2006) TribologyLetters 22: 29-36. The upper human cartilage sample had an approximately4 mm diameter and the lower human cartilage sample had an approximately6 mm diameter. Two lubricants were tested, samples 1d and 2s. 1dcorresponds to a 1% sodium hyaluronate in an isotonic salt freenon-Newtonian viscosity profile formulation, and 2s corresponds to a 1%sodium hyaluronate in the presence of isotonic saline, therefore being aNewtonian viscosity profile formulation. 10N of load was applied, at aspeed of 1 mm/s over a distance of 4 mm, with the temperature at 36-37°C.

Lubricant 2s Lubricant 1d Dynamic Static Dynamic Static Average 0.0489210/061013 0/037588 0/057958 Standard 0/013698 0/013623 0/014809 0/012595DeviationIn the presence of lubricant 2s, the cartilage samples adhered to eachother much more strongly than in the presence of lubricant 1d.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative examples and thatthe present invention may be embodied in other specific forms withoutdeparting from the essential attributes thereof, and it is thereforedesired that the present embodiments and examples be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims, rather than to the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

What is claimed is:
 1. An injectable pharmaceutical formulation for thealleviation or reduction of joint irritation or for the reduction ofworsening of existing joint inflammation as a result of furtherirritation, formulated for intra-articular injection, comprising Xylitolas the active ingredient therein.
 2. An injectable pharmaceuticalformulation according to claim 1, wherein the Xylitol is D-xylitol. 3.An injectable pharmaceutical formulation according to claim 1, whereinthe Xylitol is L-xylitol or D,L-xylitol.
 4. An injectable pharmaceuticalformulation according to claim 1, wherein the concentration of Xylitolis between 0.5% and 10% in water.
 5. An injectable pharmaceuticalformulation according to claim 1 containing at least one polymer.
 6. Aninjectable pharmaceutical formulation according to claim 1, furthercomprising an anionic polymer with molecular weight higher than 500,000dalton formulated to possess non-newtonian shear thinning viscosity. 7.An injectable pharmaceutical formulation according to claim 6, whereinthe anionic polymer is neutralized hyaluronic acid in the presence ofless than 0.01% inorganic salt.
 8. An injectable pharmaceuticalformulation according to claim 7, wherein the concentration ofneutralized hyaluronic acid is 0.1% to 5%.
 9. An injectablepharmaceutical formulation according to claim 6 wherein said anionicpolymer is in the form of a salt thereof and wherein said formulationcontains less than 0.01% of any inorganic salt.
 10. An injectablepharmaceutical formulation according to claim 1 substantially devoid ofany oil in water or wax in water emulsion.
 11. An injectablepharmaceutical formulation according to claim 1, wherein the Xylitol isin isotonic concentration.
 12. An injectable pharmaceutical formulationaccording to claim 1 further comprising at least one pharmaceuticallyacceptable excipient or additive.
 13. An injectable pharmaceuticalformulation according to claim 1, comprising at least one furtherpharmaceutical agent selected from the group consisting of ananti-inflammatory agent, an antioxidant, a vitamin, another polyol andcombinations thereof.
 14. An injectable pharmaceutical formulationaccording to claim 1, wherein said formulation consists essentially ofan active polyol ingredient, which polyol active ingredient is Xylitol.15. A method of treating a joint disease, disorder or condition, saidmethod comprising injecting a pharmaceutical composition into anaffected joint tissue, wherein said composition comprises xylitol and ananionic polymer, wherein said composition exhibits non-Newtonian shearthinning viscosity.
 16. A method of treating a joint disease, disorderdisease, disorder or condition, said method comprising injecting apharmaceutical composition into an affected joint tissue, wherein saidcomposition comprises xylitol and optionally at least a secondtherapeutic agent, wherein said second therapeutic agent comprises ananionic polymer, an anti-inflammatory agent, an antioxidant, a vitamin,a second polyol or combinations thereof.
 17. The use of xylitol and ananionic polymer in the manufacture of an injectable pharmaceuticalformulation, formulated for intra-articular injection, which compositionexhibits non-Newtonian shear thinning viscosity for the alleviation orreduction of joint irritation or for the reduction of worsening ofexisting joint inflammation.
 18. The use of xylitol and optionally atleast a second therapeutic agent, wherein said second therapeutic agentcomprises an anionic polymer, an anti-inflammatory agent, anantioxidant, a vitamin, a second polyol or combinations thereof in themanufacture of an injectable pharmaceutical formulation, formulated forintra-articular injection, which composition exhibits non-Newtonianshear thinning viscosity for the alleviation or reduction of jointirritation or for the reduction of worsening of existing jointinflammation.